- The discovery, design and synthesis of potent agonists of adenylyl cyclase type 2 by virtual screening combining biological evaluation
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Adenylate cyclases (ACs), play a critical role in the conversion of adenosine triphosphate (ATP) into the second messenger cyclic adenosine monophosphate (cAMP). Studies have indicated that adenylyl cyclase type 2 (AC2) is potential drug target for many diseases, however, up to now, there is no AC2-selective agonist reported. In this research, docking-based virtual screening with the combination of cell-based biological assays have been performed for discovering novel potent and selective AC2 agonists. Virtual screening disclosed a novel hit compound 8 as an AC2 agonist with EC50 value of 8.10 μM on recombinant human hAC2 + HEK293 cells. The SAR (structure activity relationship) based on the derivatives of compound 8 was further explored on recombinant AC2 cells and compound 73 was found to be the most active agonist with the EC50 of 90 nM, which is 160-fold more potent than the reported agonist Forskolin and could selectively activate AC2 to inhibit the expression of Interleukin-6. The discovery of a new class of AC2-selective agonists would provide a novel chemical probe to study the physiological function of AC2.
- Li, Shanshan,Song, Gao,Wang, Liang-Liang,Weng, Zhiying,Xu, Guowei,Yang, Weimin,Yang, Yanming,Yang, Yaqing,Zhang, Jiajun,Zuo, Zhili
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supporting information
(2020/02/27)
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- Synthesis and biological evaluation of novel benzylidene-succinimide derivatives as noncytotoxic antiangiogenic inhibitors with anticolorectal cancer activity in vivo
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A novel series of benzylidene-succinimide derivatives were synthesized, characterized and evaluated for their cytotoxicities against HCT116, and SW480 cancer cells and NCM460 normal human cells. Their antiangiogenic capabilities were evaluated using a chick chorioallantoic membrane (CAM) assay. The compound, XCF-37b, was selected as the most potent antiangiogenic inhibitor with noncytotoxicity to evaluate the pharmacological effects on human umbilical vein endothelial cells (HUVECs) and cancer cells in vivo and in vitro. The results showed that XCF-37b inhibited HT29-cell colon tumor growth in vivo, without showing cytotoxicity against the five other cancer cell lines in vitro. Experiments confirmed that XCF-37b had obvious antiangiogenic activity by HUVEC migration and invasion and rat aortic ring angiogenesis ex vivo. Mechanism studies showed that XCF-37b inhibited the AKT/mTOR and VEGFR2 signaling pathways, as evidenced by decreased expressions of phosphor-AKT (p-AKT), p-mTOR, p-VEGFR2 (Tyr175), p-Src (Tyr416), p-FAK (Tyr925), and p-Erk1/2 (Thr202/Tyr204). Moreover, XCF-37b significantly decreased the protein expressions of matrix metalloproteinase-2 (MMP-2), MMP-9 and hypoxia-inducible factor-1α (HIF-1α). XCF-37b generally regulated angiogenic inhibition through several regulatory pathways, without significantly interfering with colorectal cancer cell growth.
- Luo, Kaixiu,Bao, Yafeng,Liu, Feifei,Xiao, Chuanfan,Li, Ke,Zhang, Conghai,Huang, Rong,Lin, Jun,Zhang, Jihong,Jin, Yi
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p. 805 - 827
(2019/07/10)
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- Alizarin red S-TiO2-catalyzed cascade C(sp3)-H to C(sp2)-H bond formation/cyclization reactions toward tetrahydroquinoline derivatives under visible light irradiation
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A very low amount of organic dye (Alizarin red S) sensitized TiO2 and it was successfully used to catalyze cascade C(sp3)-H to C(sp2)-H bond formation/cyclization reactions under visible light irradiation. The modified TiO2 photocatalyst efficiently, for the first time, advanced [4+2] cyclization of N,N-dimethylanilines and maleimides to the corresponding tetrahydroquinolines in air atmosphere. The reaction proceeds through α-amino radicals without additional oxidant at ambient temperature to afford products in good to excellent yields.
- Hosseini-Sarvari, Mona,Koohgard, Mehdi,Firoozi, Somayeh,Mohajeri, Afshan,Tavakolian, Hosein
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supporting information
p. 6880 - 6888
(2018/05/04)
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- Solvent-free and room temperature visible light-induced C-H activation: CdS as a highly efficient photo-induced reusable nano-catalyst for the C-H functionalization cyclization of: T -amines and C-C double and triple bonds
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Nano-sized CdS was successfully prepared, fully characterized and applied as a highly efficient reusable photocatalyst for the synthesis of pyrrolo[3,4-c]quinolone and pyrrolo[2,1-a]isoquinoline-8-carboxylate derivatives through a condensation reaction of N,N-dimethylanilines or alkyl 2-(3,4-dihydroisoquinolin-2(1H)-yl)acetates with maleimides via a C-H activation approach under benign and eco-friendly conditions at room temperature without using any solvent and oxidant under visible light irradiation. Besides, the prepared photocatalyst has been successfully applied for the condensation reaction of N,N-dimethylanilines with alkyl but-2-ynedioates or phenyl acetylenes for the synthesis of novel 1,2-dihydroquinoline-3,4-dicarboxylate and aryl-1,2-dihydroquinoline derivatives for the first time. Using this method, all favourable products were obtained in good yields and relatively short reaction times under benign conditions with the application of visible light irradiation, a renewable energy source. The catalyst was easily recovered and reused several times without any loss of its activity.
- Firoozi, Somayeh,Hosseini-Sarvari, Mona,Koohgard, Mehdi
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supporting information
p. 5540 - 5549
(2019/01/03)
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- Potent Nematicidal Activity of Maleimide Derivatives on Meloidogyne incognita
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Different maleimide derivatives were synthesized and assayed for their in vitro activity on the soil inhabiting, plant-parasitic nematode Meloidogyne incognita, also known as root-knot nematode. The compounds maleimide, N-ethylmaleimide, N-isopropylmaleimide, and N-isobutylmaleimide showed the strongest nematicidal activity on the second stage juveniles of the root-knot nematode with EC50/72h values of 2.6 ± 1.3, 5.1 ± 3.4, 16.2 ± 5.4, and 19.0 ± 9.0 mg/L, respectively. We also determined the nematicidal activity of copper sulfate, finding an EC50 value of 48.6 ± 29.8 mg/L. When maleimide at 1 mg/L was tested in combination with copper sulfate at 50 mg/L, we observed 100% mortality of the nematodes. We performed a GC-MS metabolomics analysis after treating nematodes with maleimide at 8 mg/L for 24 h. This analysis revealed altered fatty acids and diglyceride metabolites such as oleic acid, palmitic acid, and 1-monopalmitin. Our results suggest that maleimide may be used as a new interesting building block for developing new nematicides in combination with copper salts.
- Eloh, Kodjo,Demurtas, Monica,Mura, Manuel Giacomo,Deplano, Alessandro,Onnis, Valentina,Sasanelli, Nicola,Maxia, Andrea,Caboni, Pierluigi
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p. 4876 - 4881
(2016/07/06)
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- α-chlorosuccinimides - A new source for maleimides and succinimides
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N-Arylmaleimides and N-arylsuccinimides were prepared by dehydrochlorination reaction of N-aryl α-chlorosuccinimides in the presence of a base and by reduction of 2-chlorosuccinimide in the presence of zinc, respectively. N-Aryl α-chlorosuccinimides were obtained by dehydration of N-aryl substituted maleamic acids in the presence of thionyl chloride. The structure of the synthesized compounds was confirmed by IR, 1H-NMR and 13C-NMR spectra.
- Gǎinǎ, Constantin,Gǎinǎ, Viorica
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p. 655 - 661
(2007/10/03)
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- Synthesis of N-Aryl/heteroaryl/-substituted-methyl-&α-(p-substituted anilino)succinimides as Antituberculosis Agents
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A series of N-Aryl/heteroaryl/substituted-methyl-α-(p-substituted anilino)succinimides (II) have been prepared and screened in vitro against H37Rv strain of Mycobacterium tuberculosis.Some of these compounds exhibit activity upto 0.39 μg/ml concentration.
- Rangnekar, V. M.,Bhamaria, R. P.,Khadse, B. G.
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p. 342 - 344
(2007/10/02)
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- Synthesis of N-Aryl/substituted-methyl/heteroaryl-&α-pyrrolidino/piperidino Succinimides as Antituberculosis Agents
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A series of N-Aryl/substituted-methyl/heteroaryl-α-pyrrolidino- and piperidino-succinimides (II) have been prepared and screened in vitro against H37Rv strain of Mycobacterium tuberculosis.Some of these compounds exhibit activity upto 1.56 μg/ml concentration.
- Rangnekar, V. M.,Lokhande, S. R.,Bhamaria, R. P.,Khadse, B. G.
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p. 1070 - 1071
(2007/10/02)
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